Heck偶联：机理、杂质和OPRD案例汇总

摘要：Heck反应机理氧化加成（oxidative addition）: R1X (R1为烯基或芳基，X=I > TfO > Br >> Cl)与Pd 0L n的加成，形成二价钯配合物中间体迁移插入（migratory-insertion）：烯键插入Pd-R1键的

Heck反应通式 芳基卤素和双键进行C-C键的偶联，一般优先反式产物

Heck反应机理 氧化加成（oxidative addition）: R1X (R1为烯基或芳基，X=I > TfO > Br >> Cl)与Pd 0L n的加成，形成二价钯配合物中间体迁移插入（migratory-insertion）：烯键插入Pd-R1键的过程； β-H的消除（syn β-hydride elimination）还原消除（reductive elimination）：加碱催化使重新得到Pd 0L 2。

Heck的杂质谱分析 钯催化芳基卤素（溴和碘）和α，β-不饱和酯，酮，酰胺，醛，丙烯腈以及芳基乙烯的C-C偶联反应。主要产物是下图结构，这里的双键可以不是端位烯烃。

钯催化芳基卤素（溴和碘）和乙烯基醚，烯丙基醇，以及其他烯烃类（没有拉电子基团）的C-C偶联反应。主要产物是下图结构，乙烯基醚类经酸解，往往用于芳环引入乙酰基。

从工艺研发的杂质角度，无论偶联底物是哪种结构，都需要评估C-C偶联的位置异构体（双键连接位置不一样）。从钯催化角度， 工艺中一定会有脱卤素杂质， 这也是所有金属催化偶联反应的共性杂质。 OPRD案例案例一

案例二 化合物2经Heck反应引入乙酰基，乙烯基醚的Heck反应经历两种复合物，π-complex A和π-complex B，分别得到副产物烯醚8和目标物酮3。专一性不好。

有研究显示， 如果体系中有水有助于得到专一的酮目标物。

案例三 主要杂质是钯催化典型的脱卤杂质4，以及杂质5和位置杂质6/7(双键端位参与反应，顺反式杂质）。

DOI: 10.1021/acs.oprd.6b00069

案例四

A mixture of (1) (150.0 kg, 305.6 mol), toluene (450 L), NMP (113 L), and N,N-diisopropylethylamine (DIPEA) (99.0 kg, 764.0 mol) was stirred at 20 °C and degassed by bubbling nitrogen through for at least 1 h. Tri(o-tolyl)phosphine (1.395kg, 4.58 mol) and Pd(OAc)2 (0.343 kg, 1.53 mol) were added.

The headspace of the reactor was degassed by evacuating and refilling with nitrogen for three cycles. Ethyl acrylate (carcinogenic! 42.8 kg, 427.8 mol) was added followed by setting the reactor’s nitrogen flow to 1−2 SCFM for at least 5 min. The reaction was slowly heated to 94−99 °C and stirred for 2 h. After the reaction was deemed complete by HPLC monitoring, the mixture was cooled to 50−60 °C, and H2O (375 L) was added.

案例五

端位烯烃和碘代物的钯催化偶联，得到目标物反式结构（trans）和位置异构杂质。 根据研究，R2结构拉电子能力越强，越有利于位置选择性。

To a 300-gal reactor was charged (13) (101.0 kg, 200.0 mol), N,N-Bis(tert-butoxycarbonyl) allylamine (22) (solution as prepared above, 220 mol), Pd2(dba)3 (1.83 kg, 2.00 mol), triethylamine (102.0 kg, 1000 mol), and iPrOH (160 gal), and the headspace was well purged with nitrogen. The reaction was heated to 78°C for 18 h.

Organic Process Research & Development 2005, 9, 440-450

案例六

Pd(OAc)2 (1.00 kg. 0.04 equiv), Xantphos (2.56 kg, 0.04 equiv), and NMP (107 kg) are charged to a nitrogen-purged reaction vessel to form the reaction catalyst. After this, Hunig’s base (43 kg, 3 equiv), and 14 (45.3 kg, 110.6 mol, 1 equiv) are added under ambient conditions. The reaction is heated to a target of 50 °C, and acetic anhydride (23 kg, 2 equiv) is added to effect acylation. Once acylation is complete (not more than 2% of 14 remaining), 2-vinylpyridine (70 kg, 6 equiv) is added. Theheating is further increased to a target of 90 °C. Once the Heck reaction is complete (typically not more than 2% of 29 remaining), the reaction mixture is cooled to a target of 50 °C.

dx.doi.org/10.1021/op400088k

案例七

4-Iodo-2,6-dimethylaniline (6) (32.9 kg, 108.3 mol), tetra-n-butyl ammonium chloride (TBAC, 15.0 kg, 54.1 mol), potassium carbonate (K2CO3, 52.4 kg, 378.9 mol), and water (100 L) were sequentially charged to the reactor.

The solution of 7 in THF (128.5 kg, 31.83 kg of 7, 135.3 mol) was charged, and the mixture was stirred for 20 min. The palladium(II) acetate (1.21 g, 5.4 mmol) was charged, and the reaction mixture was heated to 70 °C. The reaction mixture was stirred at 65−70 °C over 5 h until complete consumption of 6.

dx.doi.org/10.1021/op3003097

案例八

案例九

https://doi.org/10.1021/acs.oprd.4c00425

案例十

DOI: 10.1021/acs.oprd.0c00229

案例十一

10.1021/op700107h

案例十二化合物9为原料先Heck反应，再迪克曼缩合，Heck的两种Z/E构型都会转化成化合物8

DOI: 10.1021/acs.oprd.5b00280

案例十三（压力反应）

A nitrogenpurged 100 gal stainless steel vessel was charged with bromide 2 (10 kg, 46.51 mol), tri-o-tolylphosphine (467.2g, 6.27 mol, 0.033 equiv), palladium acetate (104.4 g, 0.465 mol, 0.01 equiv), (S)-(-)-BINAP (72.2 g, 0.0025 equiv), and acetonitrile (26 gal). Triethylamine (3.1 gal) was then added via isolated vacuum. The system was repurged with nitrogen and then pressurized to 50 psig with ethylene. The reaction mixture was heated to 90 °C, and ethylene was added to maintain 50 psig pressure. The mixture was stirred overnight (16 h) at 90 °C, at which time TLC (9.8:0.2, methylene chloride/methanol), and HPLC analysis indicated the reaction was complete.

yield 5.4 kg, 71.6% of a white solid;

分子内Heck反应

案例一

To a reactor were charged ester 19 (87 kg,166 mol), triphenylphosphine (2.177 kg, 8.3 mol), palladium(II)chloride (0.589 kg, 3.32 mol) and toluene (1060 kg). Triethylamine(22.3 kg, 220 mol) was added, and the mixture was heated at reflux until the reaction was complete (as measured by HPLC: alkene 17:ester 19

案例二

最初采用双氟底物11进行一锅法的双Heck反应构建7元环（先分子间Heck反应，再分子内Heck反应）

尽管有18%的杂质（分子间双偶联副产物），但是E-isomer（理想构型）/Z-isomer比例大约7比1，结晶后收率50%，E/Z=98/2。

改变体系浓度和丙烯酸酯的用量，均不能有效抑制分子间偶联副产物。